Sub theme 1.3
Degeneration and regeneration of tissues of the skeletal system

Goals of research: general outline
Scientific achievements
Future plans: special goals and approach
Running projects
Associated staff

Workgroup leaders   Department
dr.  P.M.  van  Hagen   Immunology
Prof.  M.  de  Jong   Nuclear Medicine
Prof.dr.  A.J.  van der  Lely   Internal Medicine
Prof. dr.  G.J.V.M.  van  Osch   Orthopaedics
Dr.  E.F.C.  van  Rossum   Internal Medicine

Goals of research: general outline

The skeletal system involves a number of connective tissues that together provide the shape and mechanical support of the human body. Aging or injury can affect these tissues and thereby hampering their function. This subtheme is concerned with the repair processes of deficient skeletal structures such as bone, cartilage or tendons. Tissue repair processes occur as a response to wounding, overloading or inflammation, but are often inappropriate and likely result in extra-cellular matrix of inferior quality. In specialized tissues, like e.g. articular cartilage, the latter contributes to progressive degeneration of the tissue.

Using a broad spectrum of multidisciplinary methods, our research projects aim to elucidate the mechanisms underlying normal physiological tissue turnover during homeostasis and processes that occur during degenerative skeletal diseases. In particular, we evaluate regenerative medicine options using tissue engineering or cell therapeutic approaches. In vitro, we are aiming to differentiate skeletal (progenitor) cells towards certain phenotypes to achieve the wanted tissue properties like e.g. the mechanically robust tissue architecture and matrix properties characteristic for articular cartilage. In addition, novel molecular targets form our basis to seek new therapeutic treatment options. In preclinical animal testing our in-vitro concepts are being tested and evaluated using novel in-vivo imaging techniques. The preclinical experiments are translated in clinical research that aims for new orthopedic regenerative intervention strategies.

Scientific achievements

Development and evaluation of imaging methods with micro-CT and micro-SPECT for in-vivo follow up of bone architecture and turnover, cartilage changes and macrophage activity in animal models for osteoporosis and osteoarthritis.

In different animal models the relation between subchondral bone response and cartilage damage after induction of osteoarthritis is investigated. Indications for interaction between the cartilage and the subchondral bone compartment are found.

Glucosamine is demonstrated to have effects on the metabolism of chondrocytes using cell and tissue culture experiments. In a clinical trial glucosamines were not effective.

Changes in tissue metabolism and composition during tendinopathies have been described and several models and analytical tools to perform translational tendon research are introduced in the group.

The effects of several growth factors (FGF-2, IGF-1, TGF-beta) and extracellular matrix components (COMP, collagen IX, glycosaminoglycans) on collagen assembly by chondrocytes and function of the newly formed matrix were studied.

Bone density and shape is being analysed in detail in both animal models and patients, using sophisticated pattern recognition models that correlate with and might predict bone and joint diseases such as osteporosis and osteoarthritis.

Future plans: special goals and approach

Modulating chondrogenesis using growth factors or pharmaceutical intervention: knowledge of embryonic development can be used to optimize culture media supplementation with e.g. growth factors or cell signaling modulators in order to control cellular phenotype and favor proper tissue formation.

Cartilage repair studies: cytokines, growth factors and/or bioactive molecular compounds that can be released by (custom-tailored) biomaterials or bone marrow derived stromal cells. The aim is to understand how certain secretable factors can be used to modulate tissue turnover in order to prevent degradation and/or stimulate regeneration.

(Molecular) skeletal imaging: imaging methods enabling us to follow bone and cartilage changes in small animal models will be used to evaluate new interventions for osteoporosis, osteoarthritis or implant fixation. In addition, special methods for cell tracking will be employed such as super-paramagnetic iron oxide labeling using MRI or heterogenic reporter gene expression using ultra-sensitive SPECT tracing.

Clinical skeletal imaging: the development of osteoarthritis will be studied using different imaging modalities in (large) cohort studies in combination with novel image analyses that enable to accurately quantify cartilage changes, bone changes and disease development. In addition, the relation between bone shape and genetics (polymorphisms) will be studied.

Most recent publications

1.      Uitterlinden EJ, Jahr H, Koevoet JL, Jenniskens YM, Bierma-Zeinstra SM, Degroot J, Verhaar JA, Weinans H, van Osch GJ. Glucosamine decreases expression of anabolic and catabolic genes in human osteoarthritic cartilage explants. Osteoarthritis Cartilage. 2006 Mar;14(3):250-7. IF: 4.0; 1/43 (Orthopedics)

2.      Jenniskens YM, Koevoet JL, de Bart ACW, Weinans H, Jahr H, Verhaar JAN, De Groot J, van Osch GJVM. Biochemical and functional modulation of the cartilage collagen network by IGF1, TGFbeta2 and FGF2. Osteoarthritis and Cartilage. 2006; Nov;14(11):1136-46 IF: 4.0; 1/43 (Orthopedics)

3.      Waarsing, JH, Day, JS, Verhaar, JAN, Ederveen, AGH, Weinans, H. Bone loss dynamics result in trabecular alignment in aging and ovariectomized rats. J. Orthop. Res. 24:926-935, 2006. IF: 2.8; 2/43 (Orthopedics)

4.      de Mos M, van El B, Degroot J, Jahr H, van Schie HT, van Arkel ER, Tol H, Heijboer R, van Osch GJ, Verhaar JA.  Achilles Tendinosis: Changes in Biochemical Composition and Collagen Turnover Rate. Am J Sports Med.  2007 Sep;35(9):1549-56  IF 3.3, 2/48 (Orthopedics)

5.      Gregory JS, Waarsing JH, Day J, Pols HA, Reijman M, Weinans H, Aspden RM. Early identification of radiographic osteoarthritis of the hip using an active shape model to quantify changes in bone morphometric features: can hip shape tell us anything about the progression of osteoarthritis? Arthritis Rheum. 56:3634-43, 2007. IF: 7.7; 1/22 (Rheumatology)

6.      Botter SM, van Osch GJ, Waarsing JH, van der Linden JC, Verhaar JA, Pols HA, van Leeuwen JP, Weinans H. Cartilage damage pattern in relation to subchondral plate thickness in a collagenase-induced model of osteoarthritis. Osteoarthritis Cartilage 16:506-14, 2008.  IF: 4.1; 1/49 (Orthopedics)

7.      Bastiaansen-Jenniskens YM, Koevoet W, de Bart AE, Zuurmond A-M, Bank RA; Verhaar JAN, DeGroot J, van Osch GJVM. TGF-beta affects collagen cross-linking independent of chondrocyte phenotype but strongly depending on physical environment. Tissue Engineering, Tissue Eng Part A. 2008 Jun;14(6):1059-66 IF 4.6, 13/144 (Biotech & applied Microbiology)

8.      Piscaer TM, Waarsing JH, Kops N, Pavljasevic P, Verhaar JA, van Osch GJ, Weinans H. In vivo imaging of cartilage degeneration using microCT-arthrography. Osteoarthritis Cartilage. 16:1011-7, 2008.  IF: 4.1; 1/49 (Orthopedics)

9.      Botter SM, Glasson SS, Hopkins B, Clockaerts S, Weinans H, van Leeuwen JP, van Osch GJ. ADAMTS5-/- mice have less subchondral bone changes after induction of osteoarthritis through surgical instability: implications for a link between cartilage and subchondral bone changes. Osteoarthritis Cartilage. 2009 May; 17(5): 636-645. IF 4.0, 1/49 (Orthopedics)

10.  Rozendaal RM, Koes BW, van Osch GJ, Uitterlinden EJ, Garling EH, Willemsen SP, Ginai AZ, Verhaar JA, Weinans H, Bierma-Zeinstra SM. Effect of glucosamine sulfate on hip osteoarthritis: a randomized trial. Ann Intern Med. 2008 Feb 19;148(4):268-77. IF 16.1, 4/107 (Medicine, General & Internal)